RAD51 Gene Family Structure and Function

Annual Review of Genetics, Journal Year: 2020, Volume and Issue: 54(1), P. 25 - 46

Published: July 14, 2020

Accurate DNA repair and replication are critical for genomic stability cancer prevention. RAD51 its gene family key regulators of fidelity through diverse roles in double-strand break repair, stress, meiosis. is an ATPase that forms a nucleoprotein filament on single-stranded DNA. has the function finding invading homologous sequences to enable accurate timely repair. Its paralogs, which arose from ancient duplications RAD51, have evolved regulate promote function. Underscoring importance, misregulation associated with diseases such as Fanconi anemia. In this review, we focus mammalian structure highlight use model systems mechanistic understanding cellular roles. We also discuss how members contributes disease consider new approaches pharmacologically inhibit RAD51.

Language: Английский

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New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 11488 - 11521

Published: July 2, 2024

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of growing number lethal targets led to significant expansion in the use lethality, far beyond poly(ADP-ribose) polymerase inhibitors used treat BRCA1/2-defective tumors. particular, molecular within DNA damage response have provided source that rapidly reached clinical trials. This Perspective focuses on most progress and their inhibitors, response, describing design associated therapeutic strategies. We will conclude by discussing current challenges new opportunities this promising field research, stimulate discussion medicinal chemistry community, allowing investigation reach its full potential.

Language: Английский

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The role of non‐coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential

Cancer Communications, Journal Year: 2021, Volume and Issue: 41(10), P. 981 - 1006

Published: July 20, 2021

Oral squamous cell carcinoma (OSCC), the eighth most prevalent cancer in world, arises from interaction of multiple factors including tobacco, alcohol consumption, and betel quid. Chemotherapeutic agents such as cisplatin, 5-fluorouracil, paclitaxel have now become first-line options for OSCC patients. Nevertheless, patients eventually acquire drug resistance, leading to poor prognosis. With discovery identification non-coding RNAs (ncRNAs), functions dysregulated ncRNAs development resistance are gradually being widely recognized. The mechanisms intricate involve efflux, epithelial-mesenchymal transition, DNA damage repair, autophagy. At present, strategies explore reversal need be urgently developed. Nano-delivery self-cellular delivery platforms considered effective overcome due their tumor targeting, controlled release, consistent pharmacokinetic profiles. In particular, combined application new technologies (including CRISPR systems) opened up horizons treatment OSCC. Hence, this review explored emerging regulatory OSCC, elucidated ncRNA-meditated discussed potential value using nanoparticles self-cells carriers

Language: Английский

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The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

Cancers, Journal Year: 2020, Volume and Issue: 13(1), P. 40 - 40

Published: Dec. 25, 2020

Recurrence of GBM is thought to be due GBMSCs, which are particularly chemo-radioresistant and characterized by a high capacity invade normal brain. Evidence emerging that modulation m6A RNA methylation plays an important role in tumor progression. However, the impact this mRNA modification poorly studied. We used patient-derived GBMSCs demonstrate expression demethylase, ALKBH5, increases radioresistance regulating homologous recombination (HR). In cells downregulated for we observed decrease GBMSC survival after irradiation likely defect DNA-damage repair. Indeed, several genes involved HR, including CHK1 RAD51, as well persistence γ-H2AX staining IR. also demonstrated study ALKBH5 contributes aggressiveness favoring invasion GBMSCs. deficient exhibited significant reduced capability relative control cells. Our data suggest attractive therapeutic target overcome invasiveness

Language: Английский

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Mitochondrial metabolism: a predictive biomarker of radiotherapy efficacy and toxicity

Journal of Cancer Research and Clinical Oncology, Journal Year: 2023, Volume and Issue: 149(9), P. 6719 - 6741

Published: Jan. 31, 2023

Language: Английский

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Regulation and pharmacological targeting of RAD51 in cancer

NAR Cancer, Journal Year: 2020, Volume and Issue: 2(3)

Published: Sept. 1, 2020

Abstract Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase incidence, whereas much drive resistance to therapy. Importantly, therapeutics targeting deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly breast and ovarian cancer. RAD51 DNA damage repair pathway. As such, understanding function regulation essential biology. This review will focus on role beyond how modulation its be exploited as therapeutic.

Language: Английский

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Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Cancers, Journal Year: 2021, Volume and Issue: 13(15), P. 3819 - 3819

Published: July 29, 2021

Cells respond to genotoxic stress through a series of complex protein pathways called DNA damage response (DDR). These monitoring mechanisms ensure the maintenance and transfer correct genome daughter cells selection repair, cell cycle regulation, programmed death processes. Canonical or non-canonical DDRs are highly organized controlled play crucial roles in stability diversity. When altered mutated, proteins these networks lead many diseases that share common features, tumor formation. In recent years, technological advances have made it possible benefit from principles DDR target eliminate cancer cells. new types treatments adapted different sensitivity could combination therapies maximal efficiency.

Language: Английский

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The Emerging Roles of Rad51 in Cancer and Its Potential as a Therapeutic Target

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: July 7, 2022

Defects in DNA repair pathways are emerging hallmarks of cancer. Accurate repairs and replications essential for genomic stability. Cancer cells require residual capabilities to the damage from replication stress genotoxic anti-tumor agents. Defective also promotes accumulation changes that eventually lead tumorigenesis, tumor progression, therapeutic resistance DNA-damaging Rad51 recombinase is a critical effector homologous recombination, which an mechanism double-strand breaks. has been found be upregulated many malignant solid tumors, correlated with poor prognosis. In multiple types, metabolism, metastasis drug resistance. Herein, we initially introduced structure, expression pattern key mediators involved recombination. Additionally, primarily discussed role metastasis, chemotherapeutic agents poly-ADP ribose polymerase inhibitors.

Language: Английский

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KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer

Advanced Science, Journal Year: 2023, Volume and Issue: 10(31)

Published: Sept. 13, 2023

One major characteristic of tumor cells is the aberrant activation epigenetic regulatory elements, which remodel transcriptome and ultimately promote cancer progression drug resistance. However, oncogenic functions mechanisms ovarian (OC) remain elusive. Here, super-enhancer (SE) elements that are aberrantly activated in OC identified it found SEs drive relative specific expression transcription factor KLF5 patients poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. associated with poor outcomes can vitro vivo. Mechanistically, forms a transcriptional complex EHF ELF3 binds to promoter region RAD51 enhance its transcription, strengthening homologous recombination repair (HRR) pathway. Notably, combination suberoylanilide hydroxamic acid (SAHA) olaparib significantly inhibits growth metastasis PARPi-resistant high KLF5. In conclusion, discovered SEs-driven key PARPi resistance; potential therapeutic strategies for resistance identified.

Language: Английский

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More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome

Science Advances, Journal Year: 2023, Volume and Issue: 9(29)

Published: July 19, 2023

Aging is a leading risk factor for cancer. While it proposed that age-related accumulation of somatic mutations drives this relationship, likely not the full story. We show aging and cancer share common epigenetic replication signature, which we modeled using DNA methylation from extensively passaged immortalized human cells in vitro tested on clinical tissues. This termed CellDRIFT, increased with age across multiple tissues, distinguished tumor normal tissue, was escalated breast tissue patients, transiently reset upon reprogramming. In addition, within-person differences were correlated predicted lifetime tissue-specific stem cell divisions risk. Our findings suggest may drive changes could push them toward more tumorigenic state.

Language: Английский

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